Pseudoachondroplasia/COMP - translating from the bench to the bedside.
Bottom Line: The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix.This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones.Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
Affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Karen.Posey@uth.tmc.edu.Show MeSH
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Mentions: Retention of mutant COMP and the presence of intracellular matrix stimulate the cell death pathway mechanisms, mediated through necroptosis, which is evidenced by increased TUNEL staining throughout the growth plate. (Posey et al., 2012). This leads to loss of chondrocytes, which translate into a reduction of tibial and femur lengths by 12% and these mice remain smaller than controls throughout life as shown in Fig. 2. Interestingly, the onset of reductions in growth in these mice roughly equates to the age at which PSACH is diagnosed (Posey et al., 2014). This D469del-COMP mouse model most faithfully recapitulates PSACH.
Affiliation: Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Karen.Posey@uth.tmc.edu.